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Pa Fan Hsiao,1–3 Sydney Peng,4 Ting-Cheng Tang,4 Shuian-Yin Lin,5 Hsieh-Chih Tsai4 1Department of Dermatology, Mackay Memorial Hospital, 2Mackay Medicine, Nursing and Management College, 3Mackay Medical College, New Taipei City, 4Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, 5National Applied Research Laboratories, Instrument Technology Research Center, Hsinchu, Taiwan Abstract: In this study, we investigated the effect of (ethylene glycol) (PEG) and PEG–oleylamine (OAm) functionalization on the skin permeation property of gold nanoparticles (GNS) in vivo. Chemisorption of polymers onto GNS was verified by a red shift in the ultraviolet–visible spectrum as well as by a change in the nanoparticle surface charge. The physicochemical properties of pristine and functionalized nanoparticles were analyzed by ultraviolet–visible spectroscopy, zeta potential analyzer, and transmission electron microscopy. Transmission electron microscopy revealed that the interparticle distance between nanoparticles increased after GNS functionalization. Comparing the skin permeation profile of pristine and functionalized GNS, the follicular deposition of GNS increased twofold after PEG–OAm functionalization. Moreover, PEG- and PEG–OAm-functionalized nanoparticles were able to overcome the skin barrier and deposit in the deeper subcutaneous adipose tissue. These findings demonstrate the potential of PEG- and PEG–OAm-functionalized GNS in serving a multitude of applications in transdermal pharmaceuticals. Keywords: skin penetration, amphiphilic copolymer, gold nanoparticle, oleylamine, poly(ethylene glycol)

Cutaneous T cell lymphomas (CTCLs), with mycosis fungoides (MF) and Sézary syndrome (SS) as the classic types, are the commonest group of primary cutaneous lymphomas. The diverse clinical manifestation and non-specific histologic findings of early lesions in CTCLs render diagnosis challenging. Treatment modalities also vary and include topical and oral medications, chemotherapy, phototherapy, and radiation therapies. Local dermatological, hemato-oncologic and radiotherapeutical experts in Taiwan convened meetings in 2023 to review and discuss the latest evidence and updates regarding diagnosis and management of CTCLs. A consensus was developed with the aim to raise awareness and understanding, provide practical guidance for early diagnosis and appropriate management, and ultimately optimize care to maximize benefits of patients., Competing Interests: Declaration of competing interest See separate submission of “Authorship & conflicts of Interest Statement Form”, (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

The 2023 consensus from the Taiwanese Dermatological Association (TDA) and Taiwan Lung Cancer Society (TLCS) addresses the management of tyrosine kinase inhibitor (TKI)-induced skin toxicities in non-small cell lung cancer (NSCLC). Providing a comprehensive overview, the consensus reflects recent advances in understanding causes and developmental processes of TKI-related skin toxicities. Aimed at guiding clinicians in Taiwan, the consensus integrates new treatment perspectives while incorporating experiences from local dermatology experts. Recommendations underwent a voting process, achieving consensus when 75% or more of experts agreed, leading to their inclusion. Approved by over 90% of participants, the recommended treatment algorithms for major skin toxicities offer valuable insights for clinicians managing TKI-associated effects in NSCLC patients., Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: The interleukin (IL)-36 pathway is a critical player in the pathogenesis of pustular psoriasis. However, therapies targeting this pathway are limited or unaffordable (e.g. the anti-IL-36 receptor antibody). AMP-activated protein kinase (AMPK), a regulator of cellular energy and metabolism, is known to participate in inflammatory diseases. However, its role in IL-36-induced skin inflammation remains unclear. Therefore, we sought to investigate the role of AMPK signals in regulating IL-36-induced responses in the skin., Experimental Approach: IL-36-stimulated primary normal human epidermal keratinocytes (NHEKs) and IL-36-injected (intradermally) BALB/c mice served as the cell and animal models, respectively. Additionally, 5-aminoimidazole-4-carboxamide riboside (AICAR) and A769662 served as AMPK activators., Key Results: AICAR and A769662 significantly suppressed the IL-36-induced IL-8 (CXCL8) and CCL20 production from NHEKs. IL-36-induced IκBζ protein expression was prominently reduced and IKK/IκBα phosphorylation was attenuated by AICAR and A769662. Conversely, AMPKα knockdown increased IκBζ protein expression and IKK/IκBα phosphorylation in IL-36-treated NHEKs. Furthermore, AICAR and A769662 enhanced IL-36-induced-IκBζ protein degradation via the proteasome-dependent but not the lysosome-dependent pathway. Pretreatment of NHEKs with IL-36 slightly suppressed the AICAR- and A769662-triggered phosphorylation of AMPK and acetyl-CoA carboxylase. In the mouse model, topical application of AICAR significantly reduced ear swelling, redness, epidermal thickening, neutrophil infiltration and inflammatory and antimicrobial peptide gene expression., Conclusion and Implications: AMPK activation suppresses IL-36-induced IL-8 and CCL20 release by regulating IκBζ expression in keratinocytes and reduces IL-36-induced skin inflammation in mice, suggesting that AMPK activation is a potential strategy for treating patients with IL-36-mediated inflammatory skin disorders., (© 2024 British Pharmacological Society.)

Currently, over 200,000 new cases of leprosy are reported annually worldwide. Although leprosy was thought to have been eradicated in Taiwan, a few new cases still occur annually. Protean clinical manifestations of leprosy and immunological reactions result in delayed diagnoses. In addition, drug-resistant leprosy is emerging and poses treatment challenges. In this retrospective study, we collected and analyzed the clinicopathological features, leprosy type, treatment response, and relapse rate of patients with leprosy in our hospital between January 2009 and November 2022. We found that 54% of patients were Indonesian, and borderline lepromatous leprosy was predominant (39%); moreover, histoid leprosy and the Lucio phenomenon were also reported. Polymerase chain reaction analysis identified four positive cases, including a dapsone-resistant (4%) case. Our findings indicated good control of leprosy and a lower rate of dapsone resistance than that reported by the World Health Organization (4% vs. 13%) from 2009 to 2015. We found that the patient profile in terms of the treatment duration, recurrence rate, systemic symptoms, and neurological symptoms did not differ between before and during the pandemic. We report the recent advances in leprosy diagnosis, drug-resistant gene mutations, post-exposure prophylaxis, vaccination, and the effect of coronavirus disease 2019 on leprosy to facilitate updated leprosy diagnosis and management.

Abstract: Acquired dermal melanocytosis (ADM) is a pigmented lesion caused by melanocytes in the dermis, and it is most often observed on the face of young and middle-aged Asian women. ADM development may be associated with melanin synthesis alterations, but little evidence of its molecular and histological alteration has yet been reported. This study aimed to evaluate ADM in different body locations using different immunohistochemical and chemical staining techniques. This retrospective case series includes consecutive patients confirmed as ADM by biopsy between 2001 and 2018. Patient data and archival images were used to determine the pattern and duration of skin lesions, as confirmed by data analysis of immunohistopathological staining of skin biopsy specimens. A total of 22 ADM patients were included with mean age at diagnosis of 47 years, and 63.6% were female. The most common site was limbs (36.4%), followed by face (27.3%), trunk (22.7%), and scalp (13.6%). Melanin levels were highest in the face and upper extremities and lowest in the trunk. All participants had perivascular distribution of dermal melanocytes, particularly on the face and limbs. The perineural distribution of dermal melanocytes was observed in the lower limbs, with prominent inflammation and fibrosis on the scalp. Dermal melanocytes expressed most markers recognizing melanocytes except for CD117. Analysis of this ADM case series has confirmed that melanin is activated by dermal melanocytes that may aggregate along blood vessels. CD117 may be a useful biomarker by which to identify the migration of epidermal melanocytes., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Urticaria is a prevalent disease with substantial physical, psychological, and economic impacts. With the advent of understandings of the disease and the emerging evidence of treatments, the international guidelines for treating urticaria have been updated in recent years. In order to update the 2014 edition of the Taiwanese Dermatological Association (TDA) consensus of urticaria, a total of 17 dermatologists with extensive experience in urticaria management were invited to and attended the TDA consensus meetings. All the specific aspects of the content were approved by at least 75% of the experts in attendance. Comparing to the former edition, several substantial modifications were made. For diagnosis, D-dimer was added as the recommended routine test in patients with chronic spontaneous urticaria. For pharmacological management, treatment suggestions were simplified. The approved-dosed, the up-dosed second-generation antihistamines, omalizumab, and cyclosporine were listed as the first-line to the fourth-line treatment, respectively. In addition, the management for patients of special considerations, such as the elderly, children, and pregnant women, were all discussed and mentioned in the consensus. We hope the updated TDA consensus can serve as a reference for all physicians and can help the physicians providing up-to-dated managements for these patients., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Thioredoxin-interacting protein (TXNIP), also known as Vitamin-D upregulated protein-1 (VDUP-1), interacts with thioredoxin to regulate redox responses and participates in diverse disorders including metabolic, cardiovascular, inflammatory and malignant diseases. Psoriasis is characterized by chronic skin inflammation and an aberrant pattern of keratinocyte differentiation. Clinically, psoriasis is associated with various cardiometabolic comorbidities but studies on TXNIP's biological role in skin disorders are limited. In this study, we investigated TXNIP expression in psoriasis and its regulation in normal human epidermal keratinocytes (NHEKs), and then explored how TXNIP regulated skin keratinocyte differentiation to determine its role in psoriasis pathogenesis. Our immunohistochemical study demonstrated extensive TXNIP expression in the upper and lower epidermis of psoriasis compared to predominant TXNIP expression in the basal layer of normal skin. 1, 25-dihydroxyvitamin D 3  suppressed but TGF-α and EGF enhanced TXNIP expression in NHEKs. An inducer of keratinocyte differentiation, phorbol 12-myristate 13-acetate (PMA), also diminished TXNIP expression, which was reversed by PKC-δ knockdown. TXNIP knockdown reduced PMA-induced involucrin and transglutaminse-1 expression, and increased p63 expression in NHEKs but did not significantly affect cell proliferation. H 2 O 2 -induced ROS production and EGFR phosphorylation decreased in NHEKs with TXNIP knockdown. Furthermore, PMA-induced PKC-δ phosphorylation, TGF-α, and EGF-triggered EGFR phosphorylation were attenuated by TXNIP knockdown. Our results unraveled the regulation and function of TXNIP expression in skin keratinocytes and the cross-regulation between TXNIP and EGFR signaling. These findings imply a role of TXNIP in psoriasis and provide insight into the possible impact of TXNIP regulators on the skin or psoriasis., (© 2022 Federation of American Societies for Experimental Biology.)

UVB dosage is generally regarded as the most critical factor that determines the severity of UVB-induced skin erythema. However, recent studies have demonstrated that different UV irradiances induce varying biological responses in mouse skin even at constant UV doses. UVB-induced inflammasome activation is particularly observed in human skin keratinocytes, which are classified as immunocompetent cells, but not in mouse skin keratinocytes, which do not express sufficient inflammasome complex components. In human skin UVB-induced sunburn reactions, NLRP1 inflammasome activation critically mediates the inflammatory responses. Here, we employed primary human skin keratinocytes to explore the impact of different irradiances of a constant UVB dosage on inflammasome activation and related inflammatory responses. Our findings indicated that low-irradiance UVB induced relatively stronger NLRP1 inflammasome activation, which manifested as more active IL-1β, IL-18 release, and enhanced procaspase-1 cleavage compared to high-irradiance UVB at the same dose. Irradiance did not influence cell lysis or the expression of inflammasome complex proteins including NLRP1, proIL-1β, proIL-18, procaspase-1, and ASC. The UVB-induced TNF-α and cyclooxygenase-2 expression was also relatively higher in keratinocytes exposed to low-irradiance UVB. Low-irradiance UVB also increased reactive oxygen species production. UVB-triggered signaling analysis revealed that low-irradiance UVB resulted in more prominent p38 and JNK activation. Therefore, our findings indicated that, in addition to the role of total dosage, irradiance crucially modulates UVB-elicited inflammation in human skin keratinocytes, thus providing novel insights into human skin photobiology., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The present study focused on the development of electric stimuli drug release carrier based on transition metal dicgalcogenides. First, tungsten disulfide (WS 2 ) was exfoliated and functionalized using thiol chemistry with various thiol-terminated ligands such as thioglycolic acid (TGA), mercaptosuccinic acid (MSA), and 2-ethanethiol (2ET). The exfoliated WS 2 underwent non-covalent coating with an electrically conductive polypyrrole (PPy) for functionalization, of which MSA-WS 2 -PPy achieved the highest 5-FU (anticancer drug) loading. An electrically-stimulated drug release experiment showed that TGA-WS 2 -PPy achieved a higher drug release (90%) than MSA-WS 2 -PPy (70%) and 2ET-WS 2 -Ppy (35%). The TGA-WS 2 -PPy exhibited swelling/recombination between PPY and MSA-WS 2 substrate under electrical stimulation, resulting in the highest 5-FU release. From the MTT assay result, there was no significant toxicity observed for TGA-WS 2 -PPy-FU on HaCaT cells, indicating the biocompatibility of TGA-WS 2 -PPy-FU in the absence of electrical stimulation. However, HaCaT cells died when incubated with TGA-WS 2 -PPy-FU under electrical stimulation. Finally, Raman mapping studies for TGA-WS 2 -PPy drug release in the skin of nude mice demonstrated that the carrier penetrated deeper into the skin of the mice while other systems failed to exhibit significant effects under electrical stimulation. The present study offers a novel approach in developing a non-invasive electrically-stimulated drug release system based on WS 2 and an externally-controlled delivery model., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The infectious bursal disease (IBD) causes immunosuppression in chicken of all ages and high mortality in young chicken, posing serious threat to poultry industry worldwide. One promising strategy for preventing this highly contagious disease is using recombinant subunit vaccine, employing VP2 subviral particles (SVP) as epitomic antigen. Analytical techniques of viral-like particles such as SDS-PAGE, western blot, or high-performance size-exclusion chromatography have been widely applied, but mostly unsatisfactory. In the present study, a simple, fast and cost-effective capillary zone electrophoresis (CZE) method with UV-detection was developed to analyze purified IBDV-SVP (expressed by Escherichia coli system) using commercial monoclonal antibody (mAb) against VP2. To find satisfying CZE conditions, injection mode, separation voltage, and separation buffer were explored. Through the modified CZE, mAb and SVP could be well separated and shown distinct peaks in the electropherogram. Furthermore, to determine the stoichiometry, the area of the mAb peak versus SVP/mAb binding ratio was plotted and indicated that 2 or 3 receptor molecules were bound per SVP. The purity and integrity of SVP and the interactions between SVP and mAb could be analyzed by the developed simple CZE-UV method in less than half hour. This CZE-UV method proved to be a valuable and useful tool in detection, characterization, and quantification of IBDV-SVP and the mAb, offering potential applications of in-process quality control of vaccine production, surveillance of serum antibody produced against IBDV infection, or vaccine immunization., (© 2018 Poultry Science Association Inc.)

Background: Giant cell elastolytic granuloma, also known as annular elastolytic giant cell granuloma or actinic granuloma, is histologically characterized by elastophagocytosis. Recent studies have revealed various clinical presentations in both sun-exposed and non-sun-exposed areas., Objectives: To clarify clinical characteristics based on case series observation., Methods: We retrospectively reviewed patients who fulfilled the pathological diagnosis criteria for giant cell elastolytic granuloma seen at Mackay Memorial Hospital from 2000 to 2014. Patient characteristics, clinical presentation, duration, associated diseases, treatment, and prognosis were analyzed., Results: A total of 22 patients were analyzed and categorized into three major variants. Eight patients with the "annular form" showed large annular lesions, which were usually associated with sun exposure. Six patients with the "papular form" presented with small papules. Eight patients in the "mixed form" group exhibited both papules and smaller annular plaques. The papular form had the youngest age of onset and shortest disease duration. The known consequences in 19 patients were resolved in seven, improved in three, recurred in four, and persisted in five patients., Conclusions: The term "giant cell elastolytic granuloma" is more appropriate because these were not completely related to actinic changes and may be nonannular. The papular form is not easily recognizable without a biopsy., (© 2017 The International Society of Dermatology.)

Neutrophilic figurate erythema (NFE) has been rarely reported. This study aimed to identify the clinical and pathological features of NFE. We retrospectively reviewed the information from diagnostic cases from 2000 to 2013. The diagnosis of NFE includes clinically annular rash, histopathologically predominant neutrophilic perivascular and interstitial infiltrate in the dermis without evidence of vasculitis, and exclusion of other known specific entities. Fifteen cases of NFE were identified, including 11 women and 4 men. The age distribution was 18-66 years (average 41). The major characteristic patterns in NFE were blistering annular erythema (5/15 patients), purpuric annular erythema with vesicles (4/15 patients), and multiple annular rash with central ring-shaped scales (4/15 patients). There was no specific predicted location and no association with a major systemic disease. Papillary dermal edema and mild-to-moderate leukocytoclasis in the upper dermis are the main histopathological features. Ten of the 15 patients had recurrent episodes. Two patients who had single episode were associated with drug reaction. Antineutrophil therapy was required to control the symptoms in 3 patients. NFE has a similar clinical course as erythema annulare centrifugum but has distinct features that can be recognized clinically. The pathologists should be aware of the entity when making the diagnosis of neutrophil-mediated inflammatory disorders. The treatment regimen for neutrophilic dermatoses may be needed to manage the skin lesions.

Background: Fibrokeratoma is a benign, cutaneous, fibrous tumor usually occurring on the digits. There is little data about their occurrence on nondigital areas and their surgical outcomes., Objectives: We sought to retrospectively characterize the distribution and surgical outcome of fibrokeratoma., Methods: We retrospectively reviewed the clinical information of patients with a histopathological diagnosis of fibrokeratoma, including age, gender, lesion site, number of lesions, symptoms and signs, history of trauma, and any recurrence., Results: We identified 124 patients diagnosed with fibrokeratoma in a 13-year period. The mean age was 42 years. There was a male predilection (2 : 1), and all lesions were solitary. Twenty patients (16%) had symptoms, and 13 patients (10%) had a history of trauma. Thirty patients (24%) had lesions on nondigital areas, including the upper and lower extremities and buttocks. The overall recurrence rate was 4% (five cases). Among them, three recurrent lesions were located on the periungual area of the toe. Nine patients (7%) had giant fibrokeratoma (>1 cm) but none recurred., Conclusion: Although most fibrokeratomas appeared on the digits, a certain number of cases (24%) were located on nondigital areas. The periungual area of the toe was the most common local recurrent site., (© 2017 The International Society of Dermatology.)

Background: Prurigo pigmentosa is a rare inflammatory dermatosis whose exact etiology is not understood yet. The purpose of this study was to provide evidence of hair follicle involvement in the pathogenesis by analyzing its clinicopathologic features., Methods: Patients who fulfilled both the clinical and histological diagnostic criteria of prurigo pigmentosa were recruited. Their histopathologic findings, clinical features and medical histories were analyzed., Results: A total of 32 confirmed patients were enrolled from 2002 to 2013. Their ages ranged from 11 to 79 years with a female predominance. Patient lesions were primarily reddish-brown and located on the back. A total of 25 patients (78%) had pathological involvement of hair follicles, either bacterial colonies in the hair follicles (21/32, 66%), folliculitis (8/32, 25%) or perifolliculitis (15/32, 47%). There was a significantly higher proportion of patients with hair follicle involvement compared with control groups with either noninflammatory (5/43, 12%, p < 0.001) or inflammatory skin diseases (12/32, 38%, p = 0.002) on the back. Minocycline was an effective antibiotic treatment either singly or in combination with steroids., Conclusions: The frequent presence of bacterial colonies along with sequelae of inflammatory changes on biopsy provides new evidence to support the theory that prurigo pigmentosa is a reactive inflammation associated with bacterial folliculitis., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The recommended use of doxycycline (DC) to broiler chicken is 100 mg/L via the drinking water and a 7-day withdrawal time (WDT). However, study of a higher dosage is desirable because of the possible increase of antimicrobial resistance and disease spectrum. Tissue DC residues exceeding the current maximum residue levels (MRL) was our major concern. Therefore, serum concentration and tissue depletion of DC hyclate after administration of 200 mg/L of DC in the drinking water for five consecutive days were studied. The steady-state DC concentration (8.3 ± 0.9 μg/mL) was reached on the third day of medication. The elimination constant (0.05 ± 0.01 1/h), half-life (14.9 ± 1.4 h), area under concentration versus time curve (81.0 ± 9.9 h·μg/mL) and mean residence time (22.7 ± 2.5 h) were obtained using a non-compartmental pharmacokinetic model. It was determined that the current 7-day WDT regulation was still legitimate for the kidney and liver as well as for the breast and leg muscles, which were estimated by linear regression analysis of the 99% upper distribution limit. The unregulated heart and gizzard were considered safe even when the lowest MRL of muscle (100 ng/g) was applied. While at the present time the extra-label use of drugs is only allowed under specific conditions, in the future it may become necessary to increase the general dosage of DC, and the current results suggest a safe range of DC hyclate in chicken; however, skin/fat tissue residues warrant further studies.

Background/aims: Cutaneous plasmacytosis is rare and still not well understood. A retrospective study was made of 9 Chinese patients with 1- to 15-year histories of biopsy-proven cutaneous plasmacytosis diagnosed between 2003 and 2015., Methods: Patient records and archival photographs helped establish the pattern and duration of skin lesions, and skin biopsy specimens provided additional data., Results: The mean age at diagnosis was 46.4 years. Two patients had lesions within 1 year of developing the disease, and 4 had lesions lasting longer than 5 years. One patient had lymphadenopathy of the neck that was later determined to be Castleman disease. Three patients had elevated IgG4 levels; only 2 had increased IgG4+ cells in skin tissues. Flexural accentuation was prominent. Four patients had elevated IgG levels, and 1, with an IgG level >5,000 mg/dL, developed systemic plasmacytosis (later confirmed as Castleman disease). The level of IgG4 subclass was related to disease duration, whereas IgG4+ plasma cells in tissues seemed irrelevant., Conclusion: Routine laboratory tests, especially measurement of IgG4 levels, may be useful for following patients with cutaneous plasmacytosis. Because of the retrospective nature of our study, we could only evaluate the results of a single IgG4 test for each patient, but the results pointed to cutaneous plasmacytosis in all 9 patients, who had different stages of the disease. Serial skin biopsies may also be helpful for gauging disease progress. Although IgG4-related disease was not established in any of these patients, long-term follow-up is warranted for all patients., (© 2017 S. Karger AG, Basel.)

The bowenoid transformation of seborrheic keratosis (SK) has rarely been reported. The purpose of this study is to identify their diagnostic immunohistochemical features and association with human papillomavirus (HPV) infection. Skin biopsy specimens of the phenomenon were retrieved from 2001 to 2010. Benign SK, Bowen disease, bowenoid papulosis, and squamous cell carcinoma were included as controls. All specimens were stained for hematoxylin and eosin, Ki-67, p21, p16, p53, and cyclin D1. Polymerase chain reaction-amplified HPV DNA was analyzed. Seventeen cases of SK with bowenoid transformation were identified. The immunohistochemical pattern of bowenoid transformation was similar to that of Bowen disease and bowenoid papulosis. The malignant cells exhibited increased expressions of p16, p21, and ki-67 and a decreased expression of cyclin D1 (P < 0.01). HPV DNA was detected in 5 cases of bowenoid transformation. In conclusion, a portion of the cases of SK with bowenoid transformation were associated with HPV infection. Selective immunohistochemical stains were helpful in the diagnosis of malignant change in these cases.

Background: Endothelial progenitor cells (EPCs) possess robust therapeutic angiogenic potential, yet may be limited in the capacity to develop into fully mature vasculature. This problem might be exacerbated by the absence of a neovascular foundation, namely pericytes, with simple EPC injection. We hypothesized that coculturing EPCs with smooth muscle cells (SMCs), components of the surrounding vascular wall, in a cell sheet will mimic the native spatial orientation and interaction between EPCs and SMCs to create a supratherapeutic angiogenic construct in a model of ischemic cardiomyopathy., Methods and Results: Primary EPCs and SMCs were isolated from Wistar rats. Confluent SMCs topped with confluent EPCs were spontaneously detached from the Upcell dish to create an SMC-EPC bi-level cell sheet. A rodent ischemic cardiomyopathy model was created by ligating the left anterior descending coronary artery. Rats were then immediately divided into 3 groups: cell-sheet transplantation (n=14), cell injection (n=12), and no treatment (n=13). Cocultured EPCs and SMCs stimulated an abundant release of multiple cytokines in vitro. Increased capillary density and improved blood perfusion in the borderzone elucidated the significant in vivo angiogenic potential of this technology. Most interestingly, however, cell fate-tracking experiments demonstrated that the cell-sheet EPCs and SMCs directly migrated into the myocardium and differentiated into elements of newly formed functional vasculature. The robust angiogenic effect of this cell sheet translated to enhanced ventricular function as demonstrated by echocardiography., Conclusions: Spatially arranged EPC-SMC bi-level cell-sheet technology facilitated the natural interaction between EPCs and SMCs, thereby creating structurally mature, functional microvasculature in a rodent ischemic cardiomyopathy model, leading to improved myocardial function.

Background: Glomus tumors are rare, benign, cutaneous neoplasms that must be excised completely to prevent recurrence., Objective: To investigate factors associated with recurrence of glomus tumors after surgery., Methods and Materials: Fifty-eight women and 17 men with digital glomus tumors underwent surgery between 1990 and 2008 at our hospital. These cases were retrospectively analyzed. RESULTS Mean age at diagnosis was 41.8, with an average diagnostic delay of 3.9 years. The tumor was located on a finger in 70 cases (right, 29; left, 41) and a toe in five (right, 3; left, 2). The tumor recurred in 13 (17%) patients. Recurrence was more likely if the tumor was skin-colored (odds ratio (OR)=31.67, 95% confidence interval (CI)=2.68-373.74, p=.006) or located within the nail matrix (OR=5.79, 95% CI=1.03-32.49, p=.046). No recurrence occurred in patients who had had preoperative magnetic resonance imaging or ultrasound studies., Conclusion: Skin-colored tumors or those in the nail matrix are at higher risk of recurrence. The authors have indicated no significant interest with commercial supporters., (© 2010 by the American Society for Dermatologic Surgery, Inc.)

There are discrepancies in findings on direct immunofluorescence (DIF) examinations for livedoid vasculopathy. We sought to assess the usefulness of DIF examinations as an adjunct to the diagnosis of livedoid vasculopathy. Clinical data and findings on DIF examinations were retrospectively collected from our immunofluorescence laboratory database on 27 patients with a histopathologic diagnosis of livedoid vasculopathy made between July 2002 and December 2008. The patterns of DIF were analyzed. Positive depositions of immunoreactants were found in 100%. A characteristic pattern of homogenous vascular deposition in both superficial and deep blood vessels was present in 96% (26/27) of specimens. The percentages of various immunoreactants were as follows: fibrinogen, 100%; complement component 3, 96%; immunoglobulin M (IgM), 85%; immunoglobulin A, 48%; and immunoglobulin G, 7%. Fibrinogen and IgM were the brightest deposits. The distinctive pattern of strong homogenous deposition of fibrinogen, complement component 3, and IgM in the superficial and deep plexuses was present in most cases of livedoid vasculopathy. This pattern provides a useful clue to its diagnosis.

Background/purpose: Incontinentia pigmenti is a rare, X-linked, dominant genodermatosis affecting skin, teeth, eyes, and central nervous system. Symptoms are associated with mutations in the nuclear factor-kappa B essential modulator (NEMO) gene on chromosome Xq28. Here, a subpopulation of Chinese patients with incontinentia pigmenti were examined to investigate the frequency and pattern of NEMO mutations, and to analyze their clinical features., Methods: From January 1996 to August 2006, 52 participants (21 probands and 31 family members) were screened for symptoms of incontinentia pigmenti and NEMO gene mutations. We designed a NEMO-specific PCR primer, referred to as In2S, to detect a deletion of exon 4-10 of the NEMO gene, which represents the mutation most frequently associated with incontinentia pigmenti. For participants without this deletion, all exons were sequenced to screen for other NEMO mutations. In addition, the clinical manifestations and family histories of the participants were analyzed., Results: Exon 4-10 was deleted in 13 probands, and one proband had a novel point mutation (G549C) in exon 5 that converted a glutamine to a histidine. Seven probands (33%) had no mutation in any of the exons of the NEMO gene. One of four participants who presented with hyperpigmentation also had the exon 4-10 deletion. One patient had a positive family history before the study took place, but no NEMO mutation was identified in any of the family members. Remarkably, the mothers of three of the probands exhibited the exon 4-10 deletion; however, their clinical manifestations were subtle and unrecognizable., Conclusion: Mutational analysis of the NEMO gene was helpful in diagnosing incontinentia pigmenti among participants with a nearly normal phenotype or an incomplete form of the disease that only caused hyperpigmentation symptoms., (2010 Formosan Medical Association & Elsevier. Published by Elsevier B.V. All rights reserved.)

We describe a case of granulomatous slack skin in a 31-year-old woman with an unusual presentation of acquired ichthyosis and muscular masses involving four limbs over 3 years. Vesicles and ulcerative skin nodules first appeared only 3 months prior to diagnosis. The diagnosis was confirmed after sequential biopsies of muscle, skin lesions, and lymph nodes, together with molecular genetic studies. The patient responded poorly to various therapies, including thalidomide, and died of doxorubicin-related cardiomyopathy.

Alopecia is an adverse effect in those patients taking aromatic anti-convulsant drugs but is rarely reported after discontinuing such medications in the convalescent status of anti-convulsant hypersensitivity syndrome (AHS). A 3-year-old boy developed alopecia areata (AA) universalis in the convalescent status of phenobarbital-induced AHS, compatible to the evidences of increased lymphocyte proliferation and increased dead cells percentages while his peripheral blood mononuclear cells were incubated with phenobarbital. Skin histology revealed peri-follicular, peri-bublar and supra-bublar lymphocyte infiltration. By searching for the key words AHS, alopecia areata (AA, punctuate absence of terminal scalp hair), AA totalis (complete absence of terminal scalp hair), and AA universalis (total loss of terminal scalp and body hair) using PubMed, only 2 cases, to date, developed alopecia in the convalescent status of phenobarbital-induced AHS. Among these 3 cases, all had favorable prognosis despite having jaundiced hepatitis. Their hair grew back after 2-3 months steroid therapy. Alopecia does rarely develop in the convalescent status of phenobarbital-induced AHS after stopping phenobarbital and its mechanism is related to lymphocyte infiltration into the peri-bulbar, supra-bulbar and peri-follicular regions.

Hydroa vacciniforme (HV) is a chronic photosensitivity disorder induced by ultraviolet radiation. Hydroa vacciniforme-like lymphoma is a rare cutaneous T-cell lymphoma occurring mainly in childhood. Recent studies have demonstrated an association between chronic latent Epstein-Barr virus (EBV) infection and both the benign skin disorder and the lymphoma. The authors report a 6-year-old boy with chronic EBV infection, HV-like skin eruptions, and chronic hepatitis. Histopathologic examination of a skin biopsy specimen demonstrated epidermal ballooning degeneration and dense superficial and deep perivascular and periappendageal lymphoid cell infiltrates extending to the fat lobules. Some blood vessels in the deep plexus were infiltrated by predominantly CD4+ and TIA-1+ cytotoxic T cells. The EBV genomes were found within tissue from three skin biopsies and peripheral blood cells. Monoclonal T-cell receptor gene rearrangement was present in skin biopsy specimens. Although no lymphoma has been found during 2 years of follow-up treatment, the possibility of lymphoma developing out of the current smoldering stage is of concern. The clinical manifestations of lymphoproliferative disorder and chronic active EBV infection are discussed.

Background/purpose: Early mycosis fungoides (MF) is difficult to distinguish from other benign inflammatory dermatoses. We evaluated clonal T-cell receptor (TCR) gamma gene rearrangement by polymerase chain reaction (PCR) as a surrogate to histologic diagnosis in early MF., Methods: Twenty paraffin-embedded skin biopsies from nine patients diagnosed with MF were included. Two multiplex PCR encompassing various Vgamma and Jgamma regions were used to detect TCRgamma gene rearrangements. Histologic diagnoses were categorized as "diagnostic", "consistent", "suggestive", or "nondiagnostic". We compared TCRgamma PCR results with histologic parameters to determine the differences between PCR-positive and PCR-negative groups., Results: TCRgamma PCR was positive in 53% (8/15) of the patch stage, in 100% (2/2) of the plaque stage, and in 100% (3/3) of the tumor stage. TCRgamma PCR was positive in 50% (4/8) of the specimens in both the diagnostic and consistent of MF groups, 71% (5/7) in the suggestive of MF group. We found that inflammation was more severe in PCR-negative specimens. Papillary dermal fibrosis was common, and differed significantly between PCR-positive and PCR-negative groups (p = 0.01). T-cell monoclonality was detected in one nondiagnostic lesion in a patient with psoriasis and MF., Conclusion: TCRgamma PCR allows the diagnosis of MF in patients with lymphocyte-poor lesions, suggestive of MF pathologically. TCRgamma PCR is more likely to be negative with moderate to severe inflammation, particularly with papillary dermal fibrosis. We suggest that the ratio of malignant clonal to reactive T-cells is critical for MF diagnosis.

We describe the case of a 13-year-old boy with stage I hypopigmented mycosis fungoides in whom minimal residual disease was detected with T-cell receptor gamma-polymerase chain reaction after the disease was in complete clinical remission. We further cloned and sequenced the T-cell receptor gamma-polymerase chain reaction product of the lesion in remission and found that the original T-cell clone still existed in decreased amounts. The patient was followed up for 3 1/2 years without any new lesions developing. The clinical significance of this residual malignant T-cell clone in mycosis fungoides remains to be elucidated.

Verruciform xanthoma is xanthomatous dermal infiltrate in a proliferating epidermal lesion and is an uncommon phenomenon. It has been reported in various neoplastic or inflammatory conditions. We report a 72-year-old man who had an asymptomatic 1-cm black nodule on his abdomen. Histopathology showed a typical acanthotic type of seborrheic keratosis characterized by basaloid keratinocyte proliferation and pseudohorn cysts. Many aggregated xanthomatized cells were seen in dermal papillae within the acanthotic epithelium. Papillomatosis, parakeratosis, and neutrophil infiltrates, the histologic features of typical verruciform xanthoma, were not seen. The foamy cells were positive for CD-68 and vimentin and negative for cytokeratin and S-100. No human papillomavirus DNA was found by nested polymerase chain reaction. The blood lipid profile was normal. The presence of verruciform xanthomatous change in seborrheic keratosis provides further evidence that verruciform xanthoma may be a reactive phenomenon occurring in common skin disorders.

The anticonvulsant carbamazepine (CBZ) frequently causes cutaneous adverse drug reactions (cADRs), including maculopapular eruption (MPE), hypersensitivity syndrome (HSS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We reported that SJS/TEN caused by CBZ is strongly associated with the HLA-B*1502 gene in Han Chinese. Here, we extended our genetic study to different types of CBZ-cADRs (91 patients, including 60 patients with SJS/TEN, 13 patients with hypersensitivity syndrome and 18 with maculopapular exanthema versus 144 tolerant controls). We used MALDI-TOF mass spectrometry to screen the genetic association of 278 single nucleotide polymorphisms (SNPs), which cover the major histocompatibility complex (MHC) region, tumor necrosis factor-alpha, heat shock protein and CBZ-metabolic enzymes, including CYP3A4, 2B6, 2C8, 2C9, 1A2 and epoxide hydrolase 1. In addition, we genotyped 20 microsatellites in the MHC region and performed HLA-typing to construct the recombinant map. We narrowed the susceptibility locus for CBZ-SJS/TEN to within 86 kb flanking the HLA-B gene on the extended B*1502 haplotype, and confirmed the association of B*1502 with SJS/TEN [Pc=1.6x10, odds ratio (OR)=1357; 95% confidence interval (CI)=193.4-8838.3]. By contrast to CBZ-SJS/TEN, HLA-B*1502 association was not observed in the MPE or HSS groups: MPE was associated with SNPs in the HLA-E region and a nearby allele, HLA-A*3101 (Pc=2.2x10, OR=17.5; 95% CI=4.6-66.5), and HSS with SNPs in the motilin gene (Pc=0.0064, OR=7.11; 95% CI=3.1-16.5) located terminal to the MHC class II genes. No SNPs in genes involved in CBZ metabolism were associated with CBZ-induced cADRs. Our data suggest that HLA-B*1502 could contribute to the pathogenesis of CBZ-SJS/TEN, and that genetic susceptibility to CBZ-induced cADRs is phenotype-specific.

Background: Cutaneous tuberculosis is especially difficult to distinguish from other granulomatous dermatoses. We used polymerase chain reaction (PCR) to evaluate the incidence of cutaneous tuberculosis and atypical mycobacterial infection in formalin-fixed, paraffin-embedded tissues with unspecified granulomatous inflammation and negative results for acid-fast bacilli (AFB), and analyzed the pattern of cutaneous tuberculosis in this group of patients., Methods: A total of 38 specimens which had been collected from 36 patients and fulfilled the criteria for tissues described above were used in this study. Two different primer pairs targeting the gene encoding for 16S ribosomal RNA (common to all mycobacteria) and the insertion sequence IS6110 (specific for M. tuberculosis complex) were used in the PCR assays. The clinical characteristics, histopathologic findings, and culture results of the patients were also analyzed., Results: Four specimens were excluded from the analysis due to the lack of internal control testing. Of the remaining 34 specimens, 22 were PCR positive for the 16S rRNA gene. Among them, 18 specimens were PCR positive for both the 16S rRNA gene and IS6110. Cutaneous tuberculosis could be diagnosed in these 18 cases (56.2%). Out of the 18 cases, there were 8 women and 10 men. The age range was 15-77 years (mean: 44.2 years). After reviewing their clinical presentation, 11 cases were considered as tuberculosis verrucosa cutis, 6 cases as lupus vulgaris, and 1 case as erythema induratum. The remaining 4 cases (12.5%) positive only for 16S rRNA gene were considered as possible atypical mycobacteria infection., Conclusions: These results show that in paucibacillary form of cutaneous tuberculosis with unclassical clinical and histological presentation, this PCR system provides rapid and sensitive detection of M. tuberculosis DNA in formalin-fixed, paraffin-embedded specimens. Cutaneous tuberculosis represents a significant proportion in specimens showing granulomatous inflammation. In areas like Taiwan, where prevalence of pulmonary tuberculosis is still high, tuberculosis verrucosa cutis and lupus vulgaris are common forms of cutaneous tuberculosis and are seen more frequently than atypical mycobacterial infection.

Pyruvate kinase (PK; EC 2.7.1.40) is a key glycolytic enzyme of Drosophila melanogaster. It catalyzes the conversion of phosphoenolpyruvate into pyruvate with the transfer of a phosphate group to ADP to form ATP. The ATP provides energy for cell growth and metabolism, and pyruvate participates in many metabolic reactions. Therefore, PK plays an important role in cell metabolism. Southern blot analysis, PCR, and sequencing were used to determine the content of a Drosophila pyruvate kinase (Pyk) genomic clone, lambdaPK61. The results indicated that the insert of lambdaPK61 comprised 8330 bp upstream of and 7186 bp downstream of the transcription start point of the Pyk gene. The size of the insert was 15,516 bp in total, which contained six genes including Pyk. Deletion mapping was applied to identify the promoter region and cis-acting elements 5' of PyK. Ten serial deletions produced by PCR were inserted upstream of the reporter gene (LacZ) to form recombinant plasmids, which were then transfected into Drosophila S2 cells. The results revealed that the regions -1475 approximately -1033 and -1033 approximately -534 of the 5' end of PyK possessed positive regulatory function for Pyk expression; i.e., increased gene expression. There were redundant putative cis-acting elements, including ecdysone response element (EcRE), E74A, and broad complex zinc finger (BRCZ) binding sites. Both E74A and BRCZ belong to the early genes regulated by ecdysone. This result suggested that Pyk might be regulated by ecdysone, directly or indirectly. However, the results of the developmental profile of Pyk expression by Northern blot analysis suggested that the effects of ecdysone on Pyk were repressive, not inductive. In addition, it was found that in these regions, there were many cis-acting elements related to egg and embryo development. Both -258 approximately -254 and -167 approximately -163 contained a CAAT box, and deletion of these regions decreased reporter gene expression. Therefore, it is suggested that both CAAT boxes are functional and that the promoter of Pyk might be located in the region of -258 approximately +109. No TATA box or downstream promoter element were identified around the transcription start site of Pyk. Additionally, PyK might share a regulatory region with an unknown neighboring gene. It was concluded that Pyk has the characteristics of a housekeeping gene.